1-chloro-n-sulfonyl-formamidines and process for their manufacture



I-CEHJURO-N-SULFONYL-FQRMAMEDINES AND The present invention relates tol-chloro-N-sulfonylformamidines of the general formula RSOzN=CNH-R (I)in which R represents an aliphatic or cycloaliphatic' hydrocarbonradical or an aromatic hydrocarbon radical which may contain assubstituents 1 or 2 alkyl groups, alkoxy groups, halogen atoms, 'acylgroups or radicals convertible into amino groups, or a phenyl-alkylradical, and R represents a saturated or unsaturated aliphatic orcycloaliphatic alkyl radical which may be interrupted by oxygen, or aphenyl-alkyl radical. These compounds are valuable starting substancesfor the synthesis of therapeutically important products and certain ofthem, showing hypoglycemic properties, can likewise be used asmedicaments.

The present invention likewise relates to the production of said1-ch1oro-Nehlfonyl-formamidines by reacting sulf onyl-thioureas of thegeneral formula RSO NH--CSNH R' in which R and R have the meanings givenabove, with phosgene or substances splitting ofi'phosgene.

The course of the reaction of the process of the present invention, forexample, can be explained as follows:

According to German patent application No. 1,119,258 laid open to publicinspection monoor poly-alkylated orarylated forrnarnidine hydrochloridesare obtained by the reaction of phosgene with the correspondingthioureas. It could, however, not be expected that sulfonyl-thioureas ofthe above-mentioned formula under the action of phosgene would lead to1-chloro N-sulfonyl-formamidines and that, for instance, it would bepossible to convert N-(4- methyl-benzenesulfonyl)-N'-n-butyl-thioureawithout difficulties and with excellent yields into 1-ch1oro-N-(4-methyl-benzenesulfonyl)-N'-n-butyl formamidine. It is known that due tothe presence of the sulfonyl radical the nature of a corresponding ureaor thiourea derivative is changed to a large extent so that compoundsshowing new properties are formed. Ureas, for example, are basiccompounds, whereas benzenesulfonyl-ureas such asbenzenesulfonyl-thioureas, are acid compounds capable of formingrelatively stable salts with bases or alkaline agents.- It can bededuced even from the properties of the isocyanates on which the ureasare based that the introduction of the sulfonyl radical brings aboutimportant changes in the reactivity of areas. For example,benzenesulfonyl-isocyanates are extremely sensitive compounds which, asregards reactivity, are far superior to alkyl-isocyanates.Benzenesulfonyl-mustard oils have not been synthesized up to now. Thisdifferent reactivity nitecl States Pate of the elementary substances isdemonstrated to a certain degree likewise by the corresponding urea orthiourea derivatives themselves. For instance, benzenesulfonyl-ureas canbe acylated with acid chlorides or anhydrides under specialcircumstances only (of. German Patent 1,046,026), whereas alkyl-ureasand aryl-ureas as well as the corresponding thio-compounds can beacylated with acid anhydrides without difiiculties by simple heating.Whereas, furthermore, according to German patent application No.1,119,852 laid open to public inspection alkyl-ureas and aryl-ureas canlikewise be converted by means'of phosgene into 1-chloro-forrnamidines,this is not possible, if benzenesulfonyl-alkyl-ureas are used even ifthe conditions are considerably varied. N-sulfonyl-N- phenyl-thioureascan likewise not be converted into corresponding l-chloro-formamidines;sulfur-containing compounds of hitherto unknown constitution beingobtained by this reaction.

As starting substances for the process according to the invention theremay be used: Benzenesulfonyl thioureas, substituted'benzenesulfonyl-thioureas especially those in which preferably one ortwo hydrogen atoms are substituted by halogen atoms, alkyl groups,alkoxy groups, acyl radicals as well as radicals which are convertibleinto the amino group, for instance acetylamino groups and nitro groups.Furthermore, there may be mentioned alkane-, phenylalkane-, naphthalene,tetrahydronaphthalene-, diphenyland phenoxy-phenyl-sulfonyl-thioureas.The above-mentioned sulfonyl-thioureas may carry at the side of themolecule opposite to the sulfonyl radical a saturated or unsaturatedaliphatic radical which may likewise be interrupted by oxygen, as wellas a phenyl-alkyl radical. There may be mentioned, for instance:N-benzenesulfonyl-N'-n-butyl-thiourea, N(4-methyl-benzenesulfonyl)-N'-n-butyi-thiourea, N(4-methyl-benzenesulfonyl)-N-cyclohexyl-thiourea, N-(4-methyl-benzenesulfonyl)-N1cyclohexyl-methyl-thiourea, N(4-chl0ro-benzenesulfonyl)-N'-n-propyl-thiourea andN-(4-acety1-benzenesulfonyl -N'-cyclohexyl-thiourea.

, The process of the present invention is suitably realized bydissolving or suspending the thiourea in an appropriate solvent, such astetrahydroiurane or benzene or another inert solvent, for instanceether, halogenated ether, or dioxane, and then introducing phosgene atroom temperature. It is of no importance whether the phosgeue is used ina molar proportion or in excess. Room temperature is favorably chosen asreaction temperature, but moderately elevated or reduced temperaturesmay likewise be-used.

It is likewise possible to proceed in a reverse manner by starting froma phosgene solution into which the thiourea is introduced. Instead ofphosgene there can likewise be used with advantage compounds which inthe course of the reaction deliver phosgene, for instance,l-chlorc-formic acid trichloromethyl ester. The desired products arelikewise obtained, although in a smaller yield, by using oxallylchloride. The-products are suitably isolated by cousiderablyconcentrating the reaction solution under reduced pressure and bycrystallizing the residue. The crude products thus obtained canimmediately be used for further reactions or they can be recrystallizedin inert solvents such as benzene.

The compounds according to the invention are easily crystallizingcompounds not capable of forming salts with acids. They arecharacterized by a noticeable reactivity. The chlorine atom linked tothe central carbon atom is extraordinarily reactive and can be exchangedunder the mildest conditions for the most various radicals. It is,forinstance, possible to convert l-chloro-N-benzenesulionyl-N-alkyl-formamidines with dilute alkalies, suitablyafter solution in an appropriate solvent,

i atentecl Feb. 9, 'lfitis such as dimethylformamide, in nearlyquantitative yield at roomtemperature into correspondingbenzenesulfonylalkyl-ureas. By causing alcohols to act thereon,favorably in the presence of a small amount of alkali metal hydroxidesolution, corresponding benzene-sulfonyl-isourea-alkali ethers areobtained. Treatment with amines gives rise to the formation ofcorresponding benzenesultonyl-guanidines.

The above-mentioned reactions of the amidines can be demonstrated, forexample, as follows:

therefore, be used for orally treating Diabetes mellitus,

The reduction of the blood sugar level attained upon oral application ofl-chloro-N-(4-methyl-benzenesulfonyl)-N'-cycloheXyl-formamidine can beseen from the following table:

RABBIT-ADMINISTERED: 400 MGJKG.

Tine in hours M 1 2 3 4 6 Reduction of blood-sugar level in percent 35-21 -17 l DOG-ADMINISTERED2 100 MGJKG.

Time in hours 1 i 2 3 4 5 6 24 Reduction of blood-Sugar level in percent-9 1G 19 -22 -25 -32 25 As medicinal compositions there are preferredtablets containing in addition to the products of the present inventionthe usual adjuvants and carrier substances, such as talc, starch,lactose, tragacanth or magnesium stearate. The following examples serveto illustrate the invention but they are not intended to limit itthereto:

EXAMPLE 1 1 -chI0r0-N-(4471ethyl-benzenesulfonyl -N-is0butylformamidine(a) 14.3 grams of N-(4-methyl-benzenesulfonyl)-N'- is'obutyl-thioureaare dissolved in 250 milliliters of absolute tetrahydroiurane. Phosgeneis introduced into the solution until saturation occurs. The'temperaturetemporarily reaches 35 C. After having blown air through thesolution,the latter is concentrated'under reduced pressure. The crystallineresidue of l-chloro-N-( t-rnethylbenzenesulfonyl) N isobutyl-formamidineobtained in nearly quantitative yield meltsat 92 C. after having beenrecrystallized from ace-tic acid ester. i

(b) 1 gram of the l-chloro formamidine thus obtained is dissolved inmethanol. Some drops of sodium hydroxide solution are added to thesolution and the whole is allowed to stand for 30 minutes at roomtemperature. After dilution with water, acidification with dilutehydrochloric acid there is obtained theN-(4-methyl-benzenesulfonyl)-N'-isobutyl-isourea-methyl-ether whichmelts at 76-77" C.

EXAMPLE 2 J -cIzl0r0-N- (4-mthyl-benzenesulfonyl)-N-cycl0hexylmethyl-formamidine (a) 16.3 grams ofN-(4-methyl-benzenesultonyl)-N'- cyclo-hexyl-methyl-thiourea aredissolved in 300 milliliters of tetrahydrofurane and phosgeneisintroduced until the solution is saturated. After treatment according toEnample l, a crystalline residue of l-chloro-N-(l-methylbenzenesulfonyl) N cycloheXyl-methyl-formamidine is obtainedwhich upon recrystallization from amixture of benzene and petroleumether melts at 94-96 C.

(b) milliliters of normal sodium hydroxide solution are poured over 3.20grams of the compoundthus obtained, and the whole is moderately heatedfor a few minutes on the steam bath. Upon addition of a further 100milliliters of water dissolution sets in. After heating for a total of10 minutes, the solution is cooled and, acidified by means of dilutehydrochloric acid.

The compound obtained in a yield of about 85-90% is identified as N (4methyl benzenesulfonyl) N-cyclohexylmethyl-urea according to meltingpoint and mixed melting point (US-179 C.).

{EXAMPLE 3 1 -chl0r0-N- (4-methyl-benzenesulfonyl)-N'-n-butyl-f0rmamidine As described in Example 1,1-chloro-N-(4-methylbenzenesulfonyl) N n butyl-formamidine is obtainedfrom 14.3 grams of N-(4-methyl-benzenesulfonyl)-N'-nbutyl-thicurea andphosgene in nearly quantitative yield.

Afterrecystallization from benzenethe compound melts at IUD-101 C.

in an analogous manner there are obtained:

l-chloro-N-(4-mcthyl-benzenesulfonyl)-N'- cyclolzexyl-formamidz'ne (a)15.6 gramsof N-(4-methyl-benzenesulfonyl)-N' cyclohexyl-thioureaare-introduced into a solution of tetrahydrofurane saturated withphosgene, whereby the reac-' tion temperature reaches about 37 C. Thereaction' mixture is left for some hours and then treated as dechlorideseparates.

. scribed in Example 1. The crudel-chloro-N-(methylbenzenesulfonyl)-N'-cyclohexyl formamidine obained innearly quantitative'yield melts at 128 130 C. after hav-.

ing been recrystallized from benzene.

In an analogous manner there are obtained:

l-chloro-N-(4-methyl-benzenesulfonyl)-N-(4'-methylcyclohexyl)-forrnamidine,and

l-chloro-N-(4-methyl-benzenesulfonyl)-N'-(4-isopropyl-cyclohexyl-formamidine.

(b) 1.0 gram of the compound thus obtained is dissolved in 30milliliters of dimethyl-formamide 5 milliliters of 2 N-sodium hydroxidesolution are added and after the mixture had been abandoned for 3 to 5hours, water is added. After acidification with hydrochloric acid acrystalline precipitate ofN-(4-methyl-benzenesulfonyl)-N'-cyclohexyl-urea is obtained. (Meltingpoint 172473 C.) I

(c) 3.3 grams of the l-chloro-formamidine obtained as described sub (a)are dissolved in 50 milliliters of benzene. A solution of 3.7 grams ofisobutylamine with EXAMPLE 5 1 -ch lorO-N-(4-chloro-benzenesulfonyl)N'-n-propyl-formamidine,

11.5 grams of N-(4-chloro-benzenesulfonyl)-N'-npropyl-thiourea aredissolved in 100 milliliters of tetrahydrofurane.

A solution of 5 grams of chloroforrnic acid trichlorornethylester in 50milliliters of tetrahydrofurane is added to the first solution. Afterstanding of the mixture overnight the solvent is drawn off under reducedpressure, and the crystalline residue of l-chloro-N-(4-chloro-benzenesulfonyl) N'-n-propyl-formamidine obtained is driedon clay. The crude product obtained in nearly quantitative yieldafterrecrystalliz'ation from benzene melts at ll3-l15 C.

In an analogous manner :there are obtained l-chloro-N-(4-bromo-benzenesulfonyl) N ethyl formamidine, l-chloro N(3-fiuoro-benzenesulfonyl) N' isobutylformamidine, l-chloro N(2-iodo-benzenesulfonyl)-N- n-hexyl-formamidine, l-chloro-N-(3 chloro 4methylbenzenesulfonyl)-N'-isoamyl formamidine, l-chloro-N- (Z-bromo 3methoxy benzenesulfonyl) N'-n-butylformamidine,l-chloro-N-(2,6-dichloro-benzenesulfonyl)- N-isopropyl-formamidine.

(EXAMPLE 6 J-chloro-N- (4-chloro-benzenesulfonyl)-N- benzyl-formamidineA suspension is formed of 17 grams ofN-(4-chlorobenzenesulfonyl)-N-benzyl-thioureain 400 milliliters ofbenzene. 10 grams of chloroformic acid-trichlorornethyl ester are addedwhile stirring. The mixture is slowly heated to 40 C. whereby it isdissolved. After additional stirring for 1 hour the solvent is drawn offunder reduced pressure. 1 chloro N(4-chloro-benzenesulfonyl)-N'-benzyl-formamidine is obtained in verygood yield as a crystalline product which after'recrystallization frombenzene melts at 114-1l6 C.

6 EXAMPLE 7 l -chl0r0-N- (4-methoxy-benzenesulfonyl) -N-y-methoxy-propyl) 0rmamidine (a) Analogously to the method described inExample 6 there is obtained from 15.9grams of N-(4methoxy-benzenesulfonyl)-N-('y-methoxy-propyl)-thiourea and 10 grams ofl-chloro-for-mic acid trichloromethyl ester the 1 chloro N (4 methoxybenzenesulfonyl) N methoxy-propyl)-formamadine in nearly quantitativeyield. After recrystallization from benzene the compound melts at 8890C.

(b) 6.4 grams of the compound obtained are suspended in 50 millilitersof glacial acetic acid. A solution containing 20 milliliters of glacialacetic acid and 1.85 grams of anhydrous sodium acetate is added to thesuspension. After a few seconds solution begins and turbidity sets in.Petroleum ether is added to the reaction mixture, the upper layer ispoured 01f and water is added to the residue whereby the mass iscrystallized. It is filtered off with suction, thoroughly washed outwith water and the N-(4- methoxy benzenesulfonyl) N ('y methoxy propyl)-isourea-O-acetyl ester (melting point -97 C.) is recrystallized frommethanol.

EXAMPLE 8 1 -chl0r0-N- (cyclohexane-sulfonyl -N'-is0butylformamidinel-chloro-N-(cyclopentane-sulfonyl)-N'-n-butylformamidine,

l-chloro-N- cyclohexyl-methane-sulfonyl -N'-is obutylformamidine,

l-c hloro-N- (cycloheptane-sulfonyl -N' allylformamidine,

l-chloro-N-(n-butane-sulfonyl) -N"-isopropyl-' formamidine,l-chloro-N-(ethane-sulfonyl)-N'-ethyl-formamidine, 1-chloro-N-(n-hexane-sulfonyl)-N'-isobutylformamidine, l-chloro-N- benzyl-sulfonyl)-N'-n-pr opyl-formamidine, l-chloro-N-(phenyl-ethane-sulfonyl)-N-isobutylformamidine.

EXAMPLE 9 1 -chlor0-N- (4-acetylaminb-benzenesulforiyl -N-isobutyl-formamidine A suspension is formed from 30 grams ofN-(4-acetylamino-benzenesulfonyl)-N'-isobutyl-thiourea in 700milliliters of benzene. 18 grams of chloroformic acid trichloromethylester are added while stirring. After a further addition of 200milliliters of diOxane and heating to 46 C. the reaction mixture isstirred for a further 3 hours. It is concentrated under reducedpressure, the residue obtained is pressed on clay and the1-chloro-N-(4-acetylamino-benzenesulfonyl)-N'-isobutyl-formamidine thusobtained is recrystallized from a mixture of dioxane and petroleumether. The compound obtained in good yield melts at 133-135 C.

I claim:

1. A compound of the formula wherein R is a member selected from thegroup consisting of alkyl having 2-6 carbon atoms, cyclOalkyl having 5-7carbon atoms, and substituted phenyl having at most two substituentsselected from the group consisting of alkyl having 1-4 carbon atoms,methoxy, halogen, and acetylamino, and R is a member selected from thegroup consisting of alkyl having 2-6 carbon atoms, cycloalkyl having 6-8carbon atoms, cyclohexyl methyl, methyl cyclohexyl, isopropylcyclohexyl, w-methoxy propyl, allyl, and benzyl.

2. 1 chloro N (4 methyl benzenesulfonyl) N'- isobutyl-formamidine.

3. 1 chloro N (4 methyl benzenesulfonyl) N'- 10cycloheXyLmethyl-formamidine.

4. 1 chloro N (4 methyl benzenesulfonyl) N'- n-butyl-formamidine.

' 5. 1 chloro N (4 methyl benzenesulfonyl) N'- cyclohexyl-formamidine.

1 6. 1 chloro N (4 methyl benzenesulfonyl) N cyclooctyl-formamidine.

7. 1 chloro N (4 chloro benzenesulfonyl) N n-propyl-formamidine.

8. 1 chloro N (4 chloro benzenesulfonyl) N- 20 benzyl-formamidine.

References Cited-in the file of this patent UNTTED STATES PATENTS2,312,404 Haack Mar. 2, 194-3 FOREIGN PATENTS 949,285 Germany Sept. 20,1956 Germany Dec. 14, 1961 1 OTHER REFERENCES King: J. Org. Chem., Vol.25, pp. 352-356 (1960).

Tosolini: Chemische Berichte, vol. 94, pp. 2731-2737 (1961).

1. A COMPOUND OF THE FORMULA R-SO2-N=C(-CL)-NH-R'' WHEREIN R IS A MEMBERSELECTED FROM THE GROUP CONSISTING OF ALKYL HAVING 2-6 CARBON ATOMS,CYCLOALKYL HAVING 5-7 CARBON ATOMS, AND SUBSTITUTED PHENYL HAVING ATMOST TWO SUBSTITUENTS SELECTED FROM THE GROUP CONSISTING OF ALKYL HAVING1-4 CARBON ATOMS, METHOXY, HALOGEN, AND ACETYLAMINO, AND R'' IS A MEMBERSELECTED FROM THE GROUP CONSISTING OF ALKYL HAVING 2-6 CARBON ATOMS,CYCLOALKYL HAVING 6-8 CARBON ATOMS, CYCLOHEXYL METHYL, METHYLCYCLOHEXYL, ISOPROPYL CYCLOHEXYL, W-METHOXY PROPYL, ALLYL, AND BENZYL.11. 1 - CHLORO - N - (4 - ACETYLAMINO -BENZENESULFONYL)N''-ISOBUTYL-FORMANIDINE.